The angiogenic growth of cities.

Describing the space-time evolution of urban population is a fundamental challenge in the science of cities, yet a complete theoretical treatment of the underlying dynamics is still missing. Here, we first reconstruct the evolution of London (UK) over 180 years and show that urban growth consists of an initial phase of diffusion-limited growth, followed by the development of the railway transport network and a consequential shift from central to suburban living. Such dynamics-which are analogous to angiogenesis in biological systems-can be described by a minimalist reaction-diffusion model coupled with economic constraints and an adaptive transport network. We then test the generality of our approach by reproducing the evolution of Sydney, Australia, from 1851 to 2011. We show that the rail system coevolves with urban population, displaying hierarchical characteristics that remain constant over time unless large-scale interventions are put in place to alter the modes of transport. These results demonstrate that transport schemes are first-order controls of long-term urbanization patterns and efforts aimed at creating more sustainable and healthier cities require careful consideration of population-transport feedbacks.

Crosstalk between genetic variability of adiponectin and leptin, glucose-insulin system and subclinical atherosclerosis in patients with newly diagnosed type 2 diabetes. The Verona Newly Diagnosed Type 2 Diabetes Study 14.

AIM: To evaluate the relationship of genetic variability of adiponectin (ADIPOQ), leptin (LEP) and leptin receptor (LEPR) genes with glucose-insulin system and markers of subclinical atherosclerosis (ATS) in patients with newly diagnosed type 2 diabetes. MATERIALS AND METHODS: In 794 subjects we performed: 1) euglycemic hyperinsulinemic clamp to assess insulin sensitivity; 2) mathematical modelling of a 5h-OGTT to estimate ß-cell function; 3) resting ECG; 4) carotid artery and lower limb artery eco-doppler sonography to identify ATS; 5) genotyping of tag-SNPs within ADIPOQ, LEP and LEPR gene. RESULTS: Regression analyses showed: 1) adiponectin levels were negatively associated with BMI, waist-to-hip ratio and triglycerides and positively with HDL and insulin sensitivity (p-all<0.03); 2) leptin levels were positively associated with BMI, HDL-cholesterol and plasma triglycerides and negatively with insulin sensitivity (p-all<0.001). Two SNPs (rs1501299 and rs2241767) within ADIPOQ gene were associated with circulating levels of adiponectin. The ADIPOQ-GAACA haplotype was associated with plasma adiponectin (p=0.034; ß=-0.24), ECG abnormalities (p=0.012; OR=2.76), carotid ATS (p=0.025; OR=2.00) and peripheral limb artery ATS (p=0.032; OR=1.90). The LEP-CTA haplotype showed an association with ischemic ECG abnormalities (p=0.017; OR=2.24). Finally, LEPR-GAACGG was associated with circulating leptin (p=0.005; ß=-0.31) and worst ß-cell function (p=0.023; ß=-15.10). Omnibus haplotype analysis showed that ADIPOQ haplotypes were associated with levels of adiponectin and common carotid artery ATS, LEP with peripheral limb artery ATS, whereas LEPR haplotypes influenced circulating levels of leptin. CONCLUSIONS: Results of this study reinforce knowledge on adipokines' role in regulating glucose metabolism; in particular highlighted the potential atherogenic role of leptin and the anti atherogenic role of adiponectin.

Climate change impacts on water sustainability of South African crop production.

Agricultural production in arid and semi-arid regions is particularly vulnerable to climate change, which, combined with projected food requirements, makes the sustainable management of water resources critical to ensure national and global food security. Using South Africa as an example, we map the spatial distribution of water use by seventeen major crops under current and future climate scenarios, and assess their sustainability in terms of water resources, using the water debt repayment time indicator. We find high water debts, indicating unsustainable production, for potatoes, pulses, grapes, cotton, rice, and wheat due to irrigation in arid areas. Climate change scenarios suggest an intensification of such pressure on water resources, especially in regions already vulnerable, with a country-scale increase in irrigation demand of between 6.5% and 32% by 2090. Future land use planning and management should carefully consider the spatial distribution and local sustainability of crop water requirements to reduce water consumption in water risk hotspots and guarantee long-term food security.

Global Soil Hydraulic Properties dataset based on legacy site observations and robust parameterization.

The representation of land surface processes in hydrological and climatic models critically depends on the soil water characteristics curve (SWCC) that defines the plant availability and water storage in the vadose zone. Despite the availability of SWCC datasets in the literature, significant efforts are required to harmonize reported data before SWCC parameters can be determined and implemented in modeling applications. In this work, a total of 15,259 SWCCs from 2,702 sites were assembled from published literature, harmonized, and quality-checked. The assembled SWCC data provide a global soil hydraulic properties (GSHP) database. Parameters of the van Genuchten (vG) SWCC model were estimated from the data using the R package 'soilhypfit'. In many cases, information on the wet- or dry-end of the SWCC measurements were missing, and we used pedotransfer functions (PTFs) to estimate saturated and residual water contents. The new database quantifies the differences of SWCCs across climatic regions and can be used to create global maps of soil hydraulic properties.

Pichia pastoris and the Recombinant Human Heterodimeric Amino Acid Transporter 4F2hc-LAT1: From Clone Selection to Pure Protein.

Heterodimeric amino acid transporters (HATs) are protein complexes composed of two subunits, a heavy and a light subunit belonging to the solute carrier (SLC) families SLC3 and SLC7. HATs transport amino acids and derivatives thereof across the plasma membrane. The human HAT 4F2hc-LAT1 is composed of the type-II membrane N-glycoprotein 4F2hc (SLC3A2) and the L-type amino acid transporter LAT1 (SLC7A5). 4F2hc-LAT1 is medically relevant, and its dysfunction and overexpression are associated with autism and tumor progression. Here, we provide a general applicable protocol on how to screen for the best membrane transport protein-expressing clone in terms of protein amount and function using Pichia pastoris as expression host. Furthermore, we describe an overexpression and purification procedure for the production of the HAT 4F2hc-LAT1. The isolated heterodimeric complex is pure, correctly assembled, stable, binds the substrate L-leucine, and is thus properly folded. Therefore, this Pichia pastoris-derived recombinant human 4F2hc-LAT1 sample can be used for downstream biochemical and biophysical characterizations.

Persistent decay of fresh xylem hydraulic conductivity varies with pressure gradient and marks plant responses to injury.

Defining plant hydraulic traits is central to the quantification of ecohydrological processes ranging from land-atmosphere interactions, to tree mortality and water-carbon budgets. A key plant trait is the xylem specific hydraulic conductivity (Kx ), that describes the plant's vascular system capacity to transport water. While xylem's vessels and tracheids are dead upon maturity, the xylem is neither inert nor deadwood, various components of the sapwood and surrounding tissue remaining alive and functional. Moreover, the established definition of Kx assumes linear relations between water flux and pressure gradient by tacitly considering the xylem as a "passive conduit". Here, we re-examine this notion of an inert xylem by systematically characterizing xylem flow in several woody plants using Kx measurements under constant and cyclic pressure gradients. Results show a temporal and pressure gradient dependence of Kx . Additionally, microscopic features in "living branches" are irreversibly modified upon drying of the xylem, thus differentiating the macroscopic definition of Kx for living and dead xylem. The findings highlight the picture of the xylem as a complex and delicate conductive system whose hydraulic behaviour transcends a passive gradient-based flow. The study sheds new light on xylem conceptualization, conductivity measurement protocols, in situ long-distance water transport and ecosystem modelling.

The making of a potent L-lactate transport inhibitor.

L-lactate is an important metabolite, energy source, and signaling molecule in health and disease. In mammals, its transport across biological membranes is mediated by monocarboxylate transporters (MCTs) of the solute carrier 16 (SLC16) family. Malfunction, overexpression or absence of transporters of this family are associated with diseases such as cancer and type 2 diabetes. Moreover, lactate acts as a signaling molecule and virulence factor in certain bacterial infections. Here, we report the rational, structure-guided identification of potent, nanomolar affinity inhibitors acting on an L-lactate-specific SLC16 homologue from the bacterium Syntrophobacter fumaroxidans (SfMCT). High-resolution crystal structures of SfMCT with bound inhibitors uncovered their interaction mechanism on an atomic level and the role of water molecules in inhibitor binding. The presented systematic approach is a valuable procedure for the identification of L-lactate transport inhibitors. Furthermore, identified inhibitors represent potential tool compounds to interfere with monocarboxylate transport across biological membranes mediated by MCTs.

From turbulence to landscapes: Logarithmic mean profiles in bounded complex systems.

We show that similarly to the logarithmic mean-velocity profile in wall-bounded turbulence, the landscape topography presents an intermediate region with a logarithmic mean-elevation profile. Such profiles are present in complex topographies with channel branching and fractal river networks resulting from model simulation, controlled laboratory experiments, and natural landscapes. Dimensional and self-similarity arguments are used to corroborate this finding. We also tested the presence of logarithmic profiles in discrete, minimalist models of networks obtained from optimality principles (optimal channel networks) and directed percolation. The emergence of self-similar scaling appears as a robust outcome in dynamically different, but spatially bounded, complex systems, as a dimensional consequence of length-scale independence.

Global convergence of COVID-19 basic reproduction number and estimation from early-time SIR dynamics.

The SIR ('susceptible-infectious-recovered') formulation is used to uncover the generic spread mechanisms observed by COVID-19 dynamics globally, especially in the early phases of infectious spread. During this early period, potential controls were not effectively put in place or enforced in many countries. Hence, the early phases of COVID-19 spread in countries where controls were weak offer a unique perspective on the ensemble-behavior of COVID-19 basic reproduction number Ro inferred from SIR formulation. The work here shows that there is global convergence (i.e., across many nations) to an uncontrolled Ro = 4.5 that describes the early time spread of COVID-19. This value is in agreement with independent estimates from other sources reviewed here and adds to the growing consensus that the early estimate of Ro = 2.2 adopted by the World Health Organization is low. A reconciliation between power-law and exponential growth predictions is also featured within the confines of the SIR formulation. The effects of testing ramp-up and the role of 'super-spreaders' on the inference of Ro are analyzed using idealized scenarios. Implications for evaluating potential control strategies from this uncontrolled Ro are briefly discussed in the context of the maximum possible infected fraction of the population (needed to assess health care capacity) and mortality (especially in the USA given diverging projections). Model results indicate that if intervention measures still result in Ro > 2.7 within 44 days after first infection, intervention is unlikely to be effective in general for COVID-19.

Channelization cascade in landscape evolution.

The hierarchy of channel networks in landscapes displays features that are characteristic of nonequilibrium complex systems. Here we show that a sequence of increasingly complex ridge and valley networks is produced by a system of partial differential equations coupling landscape evolution dynamics with a specific catchment area equation. By means of a linear stability analysis we identify the critical conditions triggering channel formation and the emergence of characteristic valley spacing. The ensuing channelization cascade, described by a dimensionless number accounting for diffusive soil creep, runoff erosion, and tectonic uplift, is reminiscent of the subsequent instabilities in fluid turbulence, while the structure of the simulated patterns is indicative of a tendency to evolve toward optimal configurations, with anomalies similar to dislocation defects observed in pattern-forming systems. The choice of specific geomorphic transport laws and boundary conditions strongly influences the channelization cascade, underlying the nonlocal and nonlinear character of its dynamics.

Expression, purification and crystallization of an SLC16 monocarboxylate transporter family homologue specific for l-lactate.

l-lactate plays an important role as metabolite and signaling molecule in eukaryotes and bacteria. Monocarboxylate transporters (MCTs) of the SLC16 solute carrier family are responsible for the transport of l-lactate across eukaryotic and bacterial cell membranes. Here we report an efficient protocol for the expression and purification of an SLC16 family homologue in milligram amounts. The purified protein is stable and can thus be used for biochemical and structural studies as shown by successful crystallization.

Structure and function of a monocarboxylate transporter homolog specific for L-lactate.

Monocarboxylate transporters play important roles in certain cancers. We have reported structures of an L-lactate-transporting solute carrier family 16 homolog with bound substrate and inhibitor. The structures show the transporter in the pharmacologically relevant outward-open conformation. Structure-function analysis provides insights into the molecular working mechanisms of ligand binding and L-lactate transport.

Mechanistic basis of L-lactate transport in the SLC16 solute carrier family.

In human and other mammalian cells, transport of L-lactate across plasma membranes is mainly catalyzed by monocarboxylate transporters (MCTs) of the SLC16 solute carrier family. MCTs play an important role in cancer metabolism and are promising targets for tumor treatment. Here, we report the crystal structures of an SLC16 family homologue with two different bound ligands at 2.54 and 2.69 Å resolution. The structures show the transporter in the pharmacologically relevant outward-open conformation. Structural information together with a detailed structure-based analysis of the transport function provide important insights into the molecular working mechanisms of ligand binding and L-lactate transport.

A renal genetic risk score (GRS) is associated with kidney dysfunction in people with type 2 diabetes.

This study aims to investigate whether renal and cardiovascular phenotypes in Italian patients with type 2 diabetes (T2D) could be influenced by a number of disease risk SNPs recently found in genome-wide association studies (GWAS). In 1591 Italian subjects with T2D: (1) 47 SNPs associated to kidney function and/or chronic kidney disease (CKD) and 49 SNPs associated to cardiovascular disease (CVD) risk were genotyped; (2) urinary albumin/creatinine (A/C) ratio, glomerular filtration rate (eGFR) and lipid profile were assessed; (3) a standard electrocardiogram was performed; (4) two genotype risk scores (GRS) were computed (a renal GRS calculated selecting 39 SNPs associated with intermediate traits of kidney damage and a cardiovascular GRS determined selecting 42 SNPs associated to CVD risk phenotypes). After correction for multiple comparisons, the renal GRS was not associated to A/C ratio (p = 0.33), but it was significantly related to decreased eGFR (p = 0.005). No association between the cardiovascular GRS and electrocardiogram was detected. Thus, in Italian patients with T2D a renal GRS might predict the decline in glomerular function, suggesting that the clock of diabetes associated CKD starts ticking long before hyperglycemia. Our data support the feasibility of gene-based prediction of complications in people with T2D.

CACNA1E variants affect beta cell function in patients with newly diagnosed type 2 diabetes. the Verona newly diagnosed type 2 diabetes study (VNDS) 3.

BACKGROUND: Genetic variability of the major subunit (CACNA1E) of the voltage-dependent Ca(2+) channel Ca(V)2.3 is associated to risk of type 2 diabetes, insulin resistance and impaired insulin secretion in nondiabetic subjects. The aim of the study was to test whether CACNA1E common variability affects beta cell function and/or insulin sensitivity in patients with newly diagnosed type 2 diabetes. METHODOLOGY/PRINCIPAL FINDINGS: In 595 GAD-negative, drug naïve patients (mean ± SD; age: 58.5 ± 10.2 yrs; BMI: 29.9 ± 5 kg/m(2), HbA1c: 7.0±1.3) with newly diagnosed type 2 diabetes we: 1. genotyped 10 tag SNPs in CACNA1E region reportedly covering ∼93% of CACNA1E common variability: rs558994, rs679931, rs2184945, rs10797728, rs3905011, rs12071300, rs175338, rs3753737, rs2253388 and rs4652679; 2. assessed clinical phenotypes, insulin sensitivity by the euglycemic insulin clamp and beta cell function by state-of-art modelling of glucose/C-peptide curves during OGTT. Five CACNA1E tag SNPs (rs10797728, rs175338, rs2184945, rs3905011 and rs4652679) were associated with specific aspects of beta cell function (p<0.05-0.01). Both major alleles of rs2184945 and rs3905011 were each (p<0.01 and p<0.005, respectively) associated to reduced proportional control with a demonstrable additive effect (p<0.005). In contrast, only the major allele of rs2253388 was related weakly to more severe insulin resistance (p<0.05). CONCLUSIONS/SIGNIFICANCE: In patients with newly diagnosed type 2 diabetes CACNA1E common variability is strongly associated to beta cell function. Genotyping CACNA1E might be of help to infer the beta cell functional phenotype and to select a personalized treatment.

Pleiotropic effects of GIP on islet function involve osteopontin.

OBJECTIVE: The incretin hormone GIP (glucose-dependent insulinotropic polypeptide) promotes pancreatic ß-cell function by potentiating insulin secretion and ß-cell proliferation. Recently, a combined analysis of several genome-wide association studies (Meta-analysis of Glucose and Insulin-Related Traits Consortium [MAGIC]) showed association to postprandial insulin at the GIP receptor (GIPR) locus. Here we explored mechanisms that could explain the protective effects of GIP on islet function. RESEARCH DESIGN AND METHODS: Associations of GIPR rs10423928 with metabolic and anthropometric phenotypes in both nondiabetic (N = 53,730) and type 2 diabetic individuals (N = 2,731) were explored by combining data from 11 studies. Insulin secretion was measured both in vivo in nondiabetic subjects and in vitro in islets from cadaver donors. Insulin secretion was also measured in response to exogenous GIP. The in vitro measurements included protein and gene expression as well as measurements of ß-cell viability and proliferation. RESULTS: The A allele of GIPR rs10423928 was associated with impaired glucose- and GIP-stimulated insulin secretion and a decrease in BMI, lean body mass, and waist circumference. The decrease in BMI almost completely neutralized the effect of impaired insulin secretion on risk of type 2 diabetes. Expression of GIPR mRNA was decreased in human islets from carriers of the A allele or patients with type 2 diabetes. GIP stimulated osteopontin (OPN) mRNA and protein expression. OPN expression was lower in carriers of the A allele. Both GIP and OPN prevented cytokine-induced reduction in cell viability (apoptosis). In addition, OPN stimulated cell proliferation in insulin-secreting cells. CONCLUSIONS: These findings support ß-cell proliferative and antiapoptotic roles for GIP in addition to its action as an incretin hormone. Identification of a link between GIP and OPN may shed new light on the role of GIP in preservation of functional ß-cell mass in humans.

Variants of GCKR affect both ß-cell and kidney function in patients with newly diagnosed type 2 diabetes: the Verona newly diagnosed type 2 diabetes study 2.

OBJECTIVE: In genome-wide association studies, performed mostly in nondiabetic individuals, genetic variability of glucokinase regulatory protein (GCKR) affects type 2 diabetes-related phenotypes, kidney function, and risk of chronic kidney disease (CKD). We tested whether GCKR variability affects type 2 diabetes or kidney-related phenotypes in newly diagnosed type 2 diabetes. RESEARCH DESIGN AND METHODS: In 509 GAD-negative patients with newly diagnosed type 2 diabetes, we 1) genotyped six single nucleotide polymorphisms in GCKR genomic region: rs6717980, rs1049817, rs6547626, rs780094, rs2384628, and rs8731; 2) assessed clinical phenotypes, insulin sensitivity by the euglycemic insulin clamp, and ß-cell function by state-of-the-art modeling of glucose/C-peptide curves during an oral glucose tolerance test; and 3) estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease formula. RESULTS: The major alleles of rs6717980 and rs2384628 were associated with reduced ß-cell function (P < 0.05), with mutual additive effects of each variant (P < 0.01). The minor alleles of rs1049817 and rs6547626 and the major allele of rs780094 were associated with reduced eGFR according to a recessive model (P < 0.03), but with no mutual additive effects of the variants. Additional associations were found between rs780094 and 2-h plasma glucose (P < 0.05) and rs8731 and insulin sensitivity (P < 0.05) and triglycerides (P < 0.05). CONCLUSIONS: Our findings are compatible with the idea that GCKR variability may play a pathogenetic role in both type 2 diabetes and CKD. Genotyping GCKR in patients with newly diagnosed type 2 diabetes might help in identifying patients at high risk for metabolic derangements or CKD.